Compositions and methods employing certain 6-substituted-imidazo(2, 1-b) thiazoles as anthelmintics



United States Patent ABSTRACT OF THE DISCLOSURE An anthelminticcomposition comprising certain 6-arylimidazole[2,l-b]thiazo1es and themethod of killing helminths by treatment with an anthelmintic amount ofsuch compounds.

This is a divisional application of copending application Ser. No.446,408, now US. Patent 3,274,209, which is a continuation-in-part ofcopending application Ser. No. 401,251, filed Oct. 2, 1964, which inturn is a continuationin-part application of Ser. No. 387,231, filedAug. 3, 1964, which in turn is a continuation-in-part application ofSer. No. 366,638, filed May 11, 1964, and all now abandoned.

This invention relates to new chemical compounds and generally to newderivatives of imidazo[2,1-b]thiazole having the formula:

a t raj I u N L 4 wherein the dotted line between the 2- and 3-positionsrepresent an optional bond, and Ar is a member selected FLOW CHART3,364,112 Patented Jan. 16, 1968 from the group consisting of thienyl,furyl, phenyl and substituted phenyl in which said substituent is amember selected from the group consisting of halo, preferably chloro,bromo and fluoro, nitro, amino and trifiuoromethyl; naphthyl, preferablya-naphthyl; and benzyl; provided that, when said Ar is benzyl, asaturated bond exists between the 2- and 3-positions of theimidaZo[2,1-b]thiazole nucleus, said substituted phenyl may bear one ormore of the aforementioned substituents although, in the preferredcompounds, the substituent is single and in the 3- position of thephenyl ring. The therapeutically acceptable acid addition salts of theforegoing compounds are also embraced within the scope of thisinvention.

If a double bond is present between the 2- and 3-posi tions, therespective compounds of this invention may be denoted as5,6-dihydro-6-Ar-imidazo[2,l-b1thiazo1es; and, when such double bond isabsent, i.e., a saturated bond exists between the 2- and 3-positions,the respective compounds may be denoted as2,3,5-6-tetrahydro-6-Ar-imidazo [2,1-b]thiazoles.

The novel compounds of this invention may be prepared by several methodsas illustrated by the reaction shown in the following flow chart.Elevated temperatures may be advantageously employed during thesereactions. Organic solvents of advantage in conducting the necessaryreac tions include 4-methyl-2-pentanone, benzene, toluene, Xylene,heptane, tetrahydrofuran, dioxane, ether and the like. Whereappropriate, solvents such as lower alkanols may be used, e.g., ethanol,butanol, 2-propanol, etc.

A preferred method comprises reacting a compound of Formula I, in whichAr is other than benzyl, with a thiazoli- (di)ne of Formula II to give a3-substituted thiazoli(di)ne of Formula III which may then be reduced tothe corresponding'carbinols of Formula IV. This reduction is car riedout with suitable reducing agents, such as an alkali metal borohydride,e.g., lithium, potassium or sodium borohydride, in the presence of asuitable organic solvent, such as, an ether, e.g., diethylether,diethylene glycol, tetrahydrofuran, etc., or an aliphatic alcohol, e.g.,methan01, ethanol, 2-propanol, 2-butanol, and the like.

(VIII) a e e Acyl s 1 Aeyl-NT l An alternative method of preparing thecompounds represented by Formula IV comprises reacting a thiazoli(di)-ne of Formula II with a compound of Formula VII. Acylation of thesecarbinols yields the corresponding compound of Formula V. The novelCompounds VI of this invention may be obtained by ring closure of eitherof the Compounds IV or V. Ring closure can be achieved by heatingCompounds IV or V with a suitable condensing agent, such as thionylchloride, phosphoroxychloride, phosphorpentachloride, zinc chloride,polyphosphoric acid, etc., and, preferably, in the presence of a loweraliphatic acid anhydride, such as acetic anhydride, propionic anhydrideand the like.

Alternatively, the Compounds VI of this invention may be prepared byring closure of an appropriately substituted ethylene diaminerepresented by Formula VIII, in which Ar may be benzyl, to yield acorresponding Z-rnercaptoimidazoline of Formula IX. This ring closuremay be achieved with appropriate sulfur-containing reactants such ascarbon disulfide, thiocyanic acid and the like. The resultingZ-mercapto-imidazoline (IX) is then treated with a compound of Formula Xto yield the 2,3,5,6-tetrahydro- 6-Ar-imidazo[2,1-b]thiazoles (VI) ofthis invention. The 5,6-dihydro-6-A-imidazo[2,I-bJthiazoles (VI) of thisinvention may be obtained by treating 2-mercapto-imidazoline (IX) withan acetaldehyde derivative of Formula XI.

As used in the foregoing reaction schemes, the dotted line represents anoptional bond; the symbol Ar is as previously indicated; the symbol Xrepresents a reactive ester of the corresponding alcohol with a stronginorganic or organic acid, such as hydrochloric acid, hydrobromic acid,sulfuric acid, p-toluene-sulfuric acid, methane sulfuric acid and thelike; the symbol Y represents oxygen or di-lower alkoxy and the symbol Rrepresents a member selected from the group consisting of hydrogen andacyl, which .acyl may be aliphatic or aromatic such as acetyl,propionyl, butyryl, benzoyl and the like, although acetyl is preferred.

Acylation of Compounds III wherein R is hydrogen to yield thecorresponding compounds wherein R is acyl may be accomplished by theusual acylation technique with appropriate acylating agents such as theanhydride of a lower aliphatic acid or an acyl halide, e.g., acetylchloride, benzoyl chloride, etc. Similar acylation technique may be usedin the acylation of Compounds IV to Compound V.

An alternative method of preparing the subject compounds in which Ar is6-(4-nitro-phenyl)- is by nitration of the corresponding 6-phenylcompounds, respectively. Subsequent reduction of the6-(4-nitro-phenyl)-c0mpound with suitable reducing agents as heretoforedescribed, or by catalytic hydrogenation, yields the corresponding 6-(4-amino-phenyl) compound.

The subject compounds may be isolated as the free bases by syntheticprocesses normally employed. These compounds, in base form, areconvertible to therapeutically active non-toxic acid addition salts bytreatment with an appropriate acid, such as, for example, an inorganicacid, such as, hydrohalic acid, i.e., hydrochloric, hydrobromic,hydroiodic acid; sulfuric, nitric or thiocyanic acid; a phosphoric acid;and organic acid; such as acetic, propionic, glycolic, lactic, pyruvic,oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric,benzoic, cinnamic, mandelic, methanesulfuric, ethanesulfuric,hydroxy-ethanesulfouic, benZene-sulfonic, p-toluenesulfonic, salicylic,paminosalicylic, 2 phenoxybenzoic or 2-acetoxybenzoic acid. Conversely,the salt form can be converted in the usual manner into the free base.

Without being bound to any theory whereby, it is believed that the ringnucleus of the subject bases may exist in the form exemplified by thestructure (VIa) and (VIb) in the flow chart, whereas the acid additionsalts may be exemplified by the following structure (XIII):

n N\ s Ar l + (XIII) wherein Z" represents the salt anion. Such formsare intended to be within the scope of this invention.

The subject novel compounds are useful as anthelmintic and have beenfound to be particularly effective, for example, against Ascaridz'agalli, Heterakis gallinae and Capillaria obsignata in chickens; againstlungworms in sheep and cattle, e. g., Dictyocaulus filaria andDictyocaulzls viviparus; against gastro-intestinal worms in sheep andcattle, e.g., Haemoncus c0nt0rt0s, Ostertagia spp., Trichostrongylus,sp., Cooperia sp., Nematoairus fillicolz's, Oesaphagostomum sp.,Stronglyoz'nes papillosus, Brmostom'um trigonocephalum, Chabertia oviriaand Trichuris ovis; and against Toxocaracards and Toxacaris leonimz indogs.

Accordingly, this invention embraces methods of killing helminths whichcomprise treating infected subjects with an effective anthelminticamount of the novel compounds described herein. For this purpose, fromabout 1 to about milligrams per kilogram of body weight may beadvantageously employed. Also included within the scope of thisinvention are anthelmintic compositions comprising an effectiveanthelmintic amount of the subject compounds in combination withsuitable carriers.

The subject compounds can be used, for example, in the form ofpharmaceutical and veterinarian preparations containing an anthelminticamount of said compounds or salts thereof in admixture or conjunctionwith a suitable organic or inorganic, solid or liquid pharmaceuticalcarrier, such as, for example, water, gelatine, lactose, starch,magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols,etc. The compositions are formulated by conventional methods and may bein any one of the conventional pharmaceutical forms, for example, fororal and parenteral administration, such as solutions, suspensions,emulsions, injectables, powders, slugs, granules, capsules, tablets andpellets, including unit dosage forms thereof, as well as otherconvenient forms which might be suitable for veterinarian rpharmaceutical use. They may be sterilized, for example, for parenteraladministration, and/ or may contain assistants such as conventionalexcipients, preserving, stabilizing, wetting, dispersing, disintegratingor emulsifying agents, fillers, buffers, basteriostats, bactericidalagents, sporicidal agents, thickening agents, preservatives, coloringagents, etc. They may also contain further veterinary or therapeuticallyuseful substances, including, for example, other known anthelminticssuch as pyrvinium pamoate, piperazine citrate, 2-,B-methoxyethylpyridineand the like. The new compounds and the anthelmintic compositionsthereof may also be used as additives and pre-mixes to animal feeds,drinking water, etc.

In such compositions and formulations, the concentration of the subjectcompounds should be at least about 0.01% by weight, preferably at leastabout 0.05%. The concentration of compound may range Widely above thesefigures, depending on the form the composition takes,

and indeed, in some cases the concentration of the compound may go ashigh as about 50%. The amount administered may also depend on theseverity of the condition being treated or on the species being treated.Generally, the compositions per dosage unit may contain at least about0.5 mg. of the subject imidazo [2,1-b] thiazoles and in some cases theamount per dosage unit may be as high as about 500 mg.

As mentioned above, compositions of the subject imida- Z0 [2,l-b]thiazoles may also contain other drugsof known veterinary utility, forexample, other anthelmintic agents such as the drug known asmethyridine. (Z- S-methoxyethylpyr-idine), which is described andclaimed per se in U.K. patent specification No. 889,748. Suchcompositions containing Z-fi-methoxyethylpyridine are valuable for theremoval of a wide range of worm infestations in sheep and cattle, areparticularly effective against worm infestations containing members ofthe Trichuris sp., and may be formulated as described above so as to besuitable for either oral or parenteral administration.

For example, such compositions suitable for oral administration may beliquid or solid compositions. Suitable liquid compositions include, forexample, aqueous concentrated solutions of the active ingredients, whichsolutions may optionally contain one or more buffers and/or stabilizingagents, for example sodium bisulfite, hydroxylamine or an acid-additionsalt thereof, for example the hydrochloride. The liquid compositionsalso include, for example solutions in a vegetable oil, for examplearachis oil, dimethylacetamide, poly-alkylene glycols. The solidcompositions include tablets, slugs, pellets or capsules, which may beformulated using conventional excipients. Alternatively, the solidcompositions may be in the form of dispersible compositions containingat least one adsor-bent solid, for example fullers earth or kieselguhr.The solid compositions may be in the form of pre-mix compositionssuitable for addition to animal foodstuffs, or in the form of medicatedanimal foodstufi compositions, for example compositions comprising theactive ingredients and animal foodstuffs. Compositions suitable forparenteral administration include, for example, sterile injectableaqueous and non-aqueous solutions or suspensions.

As preferred compositions containing the subject imidazo [2,1-b]thiazoles and Z-fi-methoxyethylpyridine, there may be mentioned, forexample, compositions containing between 50 and 200 parts by weight of2-5-methoxyethylpyridine or a salt thereof, for example thehydrochloride, and 1.0-20 parts by weight of dl-6-phenyl-2,3,5,6-tetrahydro-imidazo [2,1-b] thiazole or a salt thereof, forexample the hydrochloride. Such compositions may be formulated andadministered in such a manner that there is administered a dose of50-200 mg./kg. (of body-Weight) of Z-dmethoxyethylpyridine or a saltthereof, for example the hydrochloride, and 1.020 mg./kg. (of bodyweight) of dl-6-phenyl-2,3,5,S-tetrahydro-imidazo [2,1-b] thiazole or asalt thereof, for example the hydrochloride.

The invention may be illustrated by, although not limited to, thefollowing examples.

Example I A mixture of 4 parts of Z-imino-thiazoline, 8.3 parts ofbromo-methyl2-thieuylketone and 40 parts of absolute ethanol is stirredand refluxed for 2 hours in a water-bath. After cooling, theprecipitated hydrobromide is filtered ofi. From this salt the free baseis liberated on treating with ammonium hydroxide solution and it isextracted with chloroform. The organic extract is separated, treatedwith activated charcoal, filtered and the filtrate is first dried overmagnesium sulfate and then evaporated. The solid residue isrecrystallized from 24 parts 2-propanol, to yield2-imino-3-[(Z-thienylcarbonyl)-methyl]-thiazoline; M.P. 117.5-118.5 C.

Example I! A mixture of 4 parts of2-imino-3-[(Z-thionyl-carbonyl)-methyl]-thiazoline, 50 parts of aceticanhydride and 1.15 parts of sodium acetate is stirred and refluxed for15 minutes. The formed sodium bromide is filtered off. From thefiltrate, the excess of acetic anhydride is distilled and the residualsolid is recrystallized from Z-propanol. The solid is filtered oif anddried in vacuo, yielding 2- (acetyl imino) 3l(Z-thienyl-carbonyl)-methyl]-thiazoline; M.P. 146-1475 C.

Example Ill To a stirred mixture of 13 parts of 2-(acetyl-irnino)- 3 [(2thienyl-carbonyl)-methyl]-thiazoline hydrobromide and 64 parts ofethanol are added portionwise 3 parts of sodium borohydride (exothermicreaction). After the addition is complete, the whole is stirred andrefluxed for one hour. The solvent is evaporated. The solid residue isdissolved in hydrochloric acid 4 N. After keeping at room temperature,it crystallizes again. The solid is filtered off and dissolved in water.The aqueous solution is rendered alkaline with ammonium hydroxide andextracted with chloroform. The chloroform extract is dried overmagnesium sulfate and evaporated. The solid residue is recrystallizedtwice: first from 4-methyl-2- pentanone and once more from 400 parts ofwater. After drying in vacuo, dLZ-(acetyl-imino)-3-[2-hydroxy-2-(2-thienyl)-ethyl]-thiazoline is obtained; M.P. 132.5- 133 C.

Example IV A solution of 2 parts ofdl-2-(acetylimino)-3[2-hydroxy-2-(2-thienyl)-ethyl]-thiazoline in 16parts of thionylchloride and 45 parts chloroform is stirred and refiuxedfor one hour. After coolingthe whole is extracted with water. The acidaqueous solution is separated, washed with toluene, alkalized withammonium hydroxide solution and extracted with chloroform. The extractis dried over magnesium sulfate and evaporated. The oily residue isdissolved in 40 parts boiling 2-propanol. To this warm solution is addeda warm solution of an equivalent quantity of oxalic acid dihydrate in2-propanol. After cooling to room temperature, the precipitated oxalateis filtered oil and dried in vacuo, yielding dl-5,6-dihydro-6-(2-thienyl)-imidazo [2,1-b] thiazole oxalate; M.P. 192193 C.

Example V A mixture of 6 parts dl-2-(acetyl-imino)-3-[2-hydroxy-2-(Z-thienyl)-ethyl]-thiazoline and parts phosphoroxychloride is heatedin a water-bath for 2 hours at a temperature of C. After cooling, thereaction mixture is poured into water. The whole is alkalized withammonium hydroxide solution and extracted with toluene. The extract isdried over magnesium sulfate and evaporated in vacuo. The oily residueis dissolved in 40 parts boiling 2-propanol. To this warm solution isadded a Warm solution of an equivalent quantity of oxalic acid dihydratein 2-propauol. After cooling to room temperature, the precipitated saltis filtered ofi:- and dried in vacuo, yielding dl-5,6-dihydro-6(Z-thienyl) imidazo [2,1-b] thiazole oxalate; M.P. 193194 C.

An aqueous solution of this salt is alkalized with am monium hydroxideand extracted with toluene. The extract is dried over magnesium sulfateand evaporated. The oily residue is crystallized from 12 parts xylene.The solid is filtered off and dried in vacuo, yielding dl-5,6-dihydro-6-(2-thienyl)-imidazo [2,l-b] thiazole; M.P. 58.62 C.

Example VI To a solution of 1.2 parts of dl-5,6-cli hydroF6-(2-thienyl)-imidazo [2,l-b] thiazole in 24 parts acetone is added a slightexcess of a solution of hydrogen chloride in 2-propanol. The oilyprecipitate solidifies on seeding with the solid hydrochloride salt andscratching. The salt is filtered off and dried, to yielddl-5,6-dihydro-6-(2- thienyl)-imidazo [2,1-b] thiazole hydro chloride;M.P. 159160.5 C.

Example V11 To a solution of 1.2 parts dl-5,6-dihydro-6-(2-thienyl)-imidazo [2,1-b] thiazole in 24 parts acetone is added an excess ofhydrobromic acid in 2-propanol. Upon saturation, the solvent is decantedand the oily residue is crystallized from 20 parts dimethylformamide.The solid salt is filtered off and dried in vacuo, yielding dl-5,6-dihydro-G-(Z-thienyl)-imidazo [2,1-b] thiazole hydrobromide; M.P. 163164C.

Example VIII To a solution of 1.2 parts dl-5,6-dihydro-6-(Z-thienyl)-imidazo [2,1b] thiazole in 24 parts acetone is added an excess ofphosphoric acid in acetone. The solvent is decanted from the oilyprecipitate, which is then crystallized from 20 partsdimethylformarnide. The solid salt is filtered off and dried in vacuo,yielding dl-5,6-dihydro- 7 6-(2-thienyl)-irnidazo [2,1-b] thiazolephosphate; M.P. 184185 C.

Example IX To a solution of 0.42 part of dl-5,6-dihydro-6-(2-thienyl)-imidazo [2,1-b] thiazole in 20 parts ether is added a solutionof 0.235 part maleic acid in 4 parts ethanol, whereupon a precipitate isformed gradually. After standing for about 18 hours in a refrigeratorthe solid is filtered off and dried, yielding dl-5,6-dihydro-6-(2-thienyl)-imidazo [2,1-b] thiazole maleate; M.P. 109.2- 11 0.8 C.

Example X To a solution of 0.42 part of dl-5,6-dihydro-6-(2-thienyl)-imidazo [2,1-b] thiazole in 20 parts ether is added a solutionof 0.21 part malonic acid in 4 parts ethanol, whereupon a precipitate isformed gradually. After standing for about 18 hours in a refrigerator,the solid is filtered off and dried, yielding dl-5,6-dihydro-6-(Z-thienyD-imidazo [2,1-b] thiazole malonate; M.P. 95.6 97.4 C. (dec.).

Example XI A mixture of 12 parts of 2-imino-thiazoline, 23.5 parts ofbromo-methyl-2-furyl-ketone and 160 parts of 2-propanel is stirred whileheating in an oil-bath for 15 minutes at 100 C. After cooling, theformed precipitate is filtered off and dried in vacuo, yielding2-imino-3-[(2- furyl-carbonyl)-methyl]-thiazoline hydrobromide; M.P.198198.5 C.

Example XII A mixture of 55 parts of 2-imino-3-[(2-furyl-carbonyl)-methyl]-thiazoline hydrobromide, 300 parts of acetic anhydride'and 25parts of sodium acetate is stirred and refluxed for 15 minutes. Theexcess acetic anhydride is evaporated. The solid residue is alkalizedwith ammonium hydroxide and extracted with chloroform. The whole isboiled with activated charcoal, filtered and the filtrate is evaporated.The solid residue is recrystallized from 160 parts of4-methyl-2-pentanone. The solid is filtered off and dried, yielding2-(acetyl-imino)-3-[(Z-furyl-carbonyl)'-methyl]-thiazoline; M.P.142.5143.5 C.

Example XIII To a suspension of parts of 2-(acetyl-imino)-3-[(Z-furyl-carbonyl)-methyl]-thiazoline in 160 parts of ethanol are addedportionwise 3.1 parts of sodium borohydride (exothermic reaction). Afterthe addition is complete, the Whole is stirred and refluxed for onehour. The solvent is evaporated. The solid residue is decomposed withdiluted hydrochloric acid. The obtained solution is alkalized withammonium hydroxide solution, whereupon a solid is formed. It is filteredoff and recrystallized from 80 parts of toluene, yieldingdl-2-(acetyl-imino)-3- [2-(2-furyl)-2 hydroxy-ethyl] thiazoline; M.P.115- 116.5 C.

Example XIV A solution of 8 parts dl-2-'(acetyl-imino) -3-[2-(2-furyl)-2-hydroxy-ethyl]-thiazoline in 12.8 parts of thionyl chloride and120 parts of chloroform is stirred and refluxed for one hour. Aftercooling, the whole is extracted with water. The acid aqueous solution isseparated, washed with toluene, alkalized with ammonium hydroxidesolution and extracted with toluene. The extract is dried over magnesiumsulfate and evaporated. The oily residue is dissolved in boiling2-propanol. To this hot solution is added a Warm solution of anequivalent quantity of oxalic acid dihydrate in 2-propanol. Aftercooling to room temperature, the precipitated salt is filtered off anddried in vacuo, yielding d1 5,6 dihydro 6 (2 furyl imidazo [2,1-b]thiazolo oxalate; M.P. 166-173 C. (dec.).

8 Example XV A mixture of 21 parts of 2-irnino-3-(benzoybmethyl)-thiazoline hydrobromide, 200 parts of acetic anhydride' and 8 partssodium acetate is stirred and refluxed for one hour. The excess ofacetic anhydride is evaporated. The residue is alkalized with ammoniumhydroxide solution 10%. The formed solid is filtered off andrecrystallized from parts toluene, yielding 2 (acetyl imino)-3-(benzoyl-methy1)-thiazoline; M.P. 153-154 C.

Example XVI To a solution of 15 parts of2-(acetyl-imino)-3-(benzoyl-methyl)-thiazoline in parts of ethanol areadded portionwise 2.7 parts sodium borohydride (slightly exothermicreaction). After the addition is complete, the whole is stirred andrefluxed for one hour. The olvent is evaporated. The solid residue isdecomposed with hydrochloric acid and filtered. The filtrate isalkalized with ammonium hydroxide solution, whereupon a precipitate isformed. It is filtered off (filtrate is set aside) and recrystallizedfrom 80 parts Z-propanol, filtered off again and dried, yielding a firstfraction of dl-2-(acetyl-imino)-3-(B- hydroxy-phenethyl)-thiazoline;M.P. 157159 C.

The filtrate (which was set aside) is concentrated to half its volume.After cooling to 0 C., the formed precipitate is filtered off and dried,yielding a second fraction of dl 2 (acetyl imino) 3 3 hydroxyphenethyl)- thiazoline; M.P. 158-159" C.

Example XVII A solution of 4 parts ofdl-2-(acetyl-imino)-3-(fl-hydroxy-phenethyl)-thiazoline in 6.4 partsthionyl chloride and 60 partschloroform is stirred and refluxed for 2hours. After cooling the whole is extracted with water. The acid layeris washed with toluene, alkalized with ammonium hydroxide solution andextracted with chloroform. The extract is dried over magnesium sulfateand evaporated. The oily residue is dissolved in 8 parts boiling2-propanol. To this hot solution is added a warm solution of anequivalent quantity of oxalic acid dihydrate in 2-propanol. Aftercooling to room temperature, the salt is filtered off and dried,yielding dl-5,6-dihydro-6 phenyl-imidazo [2,1-b] thiazole oxalate; MP.185.5 C. (dec.).

Example XVIII To a mixture of 75 parts ofdl-2-imino-3-(18-hydroxyphenethyl)-thiazoline hydrobromide and 184 partsof thionylchloride are added carefully 600 parts of acetic anhydride,while cooling in an ice-bath. When a homogenous mixture is obtained, thecooling-bath is removed and the whole is stirred and refluxed for 10minutes. Then the second part of 96 parts of thionyl chloride is addedpertionwise and the whole is stirred and refluxed foranother 30 minutes.The formed acetylchloride is distilled off (internal temperature: 137C.). The residue is evaporated in vacuo. The residue is dissolved in amixture of 800 parts of water and 80 parts of concentrated hydrochloricacid. After standing for 30 minutes, the mixture is filtered from someinsoluble matter and the filtrate is'alkalized with 200 parts Olfammonium hydroxide and then extracted with toluene (successively: 120.80and 80 parts). The combined extracts are dried over magnesium sulfate,filtered, washed with parts toluene and the filtrate is evaporated invacuo. The residue is dissolved in a boiling mixture of 32 parts2-propanol and 16 parts hexane. To this hot solution is added a hotsolution of 31 parts oxalic acid dihydrate in 40 parts 2-propano1. Aftercooling to 4 C., the solid salt is filtered oif, washed on the filterwith 2 propanol and dried, yielding dl 5,6 dihydro 6- phenyl-imidazo[2,1-b] thiazole oxalate; MP. 1868-- 187.5 C. (dec.).

9 Example XIX From 25.2 parts of dl-p-amino-phenethyl-aminedihydrochloride the free base is liberated as follows: 25.2 partsdl-B-amino-phenethyl-amine dihydrochloride are dissolved in 40 partswater. This solution is alkalized with 9.6 parts of sodium hydroxide andextracted with ethanol. The precipitated sodium chloride is filtered offand to the filtrate are added 8.15 parts carbon disulfide (exothermicreaction). The mixture is stirred and refluxed for one hour in anoil-bath. Then there is added one part concentrated hydrochloric acidand the mixture is further stirred and refluxed for hours. The reactionmixture is stirred overnight at room temperature. The precipitatedproduct is filtered off, washed with water and acetone and dried,yielding dl 2 thio 4 phenyl imidazolidine; M.P. 194-1955 C.

To a solution of sodium ethoxide, prepared in the usual manner startingfrom 0.46 part of sodium in 80 parts of ethanol, are added 3.6 parts ofdl-2-thio-4-phenylimidazolidine. After the addition is complete, thewhole is stirred and refluxed for minutes. Then there are added 3.1parts of chloroacetaldehyde-diethylacetal. The mixture is stirred andrefluxed for one hour. After cooling, the ethanol is evaporated. To theresidue are added 28 parts of concentrated hydrochloric acid and theunreacted starting material is filtered off. After refluxing thefiltrate for one hour, the hydrochloric acid is evaporated. The residueis redissolved in parts of water. The aqueous solution is alkalized withammonium hydroxide and extracted with chloroform. The extract is driedand evaporated. The residue is dissolved in 20 parts boiling 2-propanol.To this hot solution is added a warm solution of an equivalent quantityof oxalic acid dihydrate in 20 parts of 2-propanol. After cooling toroom temperature, the precipitated oxalate salt is filtered otf andrecrystallized from parts of boiling 2-propanol. After cooling, thesolid oxalate is filtered off, washed successively with 2-propanol andether, and dried, yielding dl 5,6 dihydro 6 phenyl imidazo [2,1-b]thiazole oxalate; M.P. 183184.5 C.

Example XX A mixture of 62 parts ofdI-Z-(acetyl-imino)-3-(;3-hydroxyphenethyl)-thiazoline and 208 parts ofphosphoroxychloride i boiled for 1 h., in a boiling Water-bath. Aftercooling the reaction mixture is poured into a mixture of Water andcrushed ice. The whole is alkalized with ammonium hydroxide andextracted with toluene. The extract is dried over magnesium sulfate andevaporated. The oily residue is dissolved in 40 parts acetone andgaseous hydrogen chloride is introduced into the solution. Theprecipitated salt is filtered 0E and dried, yieldingdl-5,6-dihydro-6-phenyl-imidazo [2,1-b] thiazole hydrochloride; M.P.175-177 C.

Example XXI 137 parts of dl-5,6-dihydro-6-phenyl-imidazo [2,l-b]thiazole oxalate are dissolved in a mixture of 1500 parts of water and100 parts of concentrated hydrochloric acid, while stirring. Thesolution is filtered over hyflo and the filtrate is alkalized withammonium hydroxide and extracted several times with chloroform(successively: 375, 225 and 150 parts). The combined extracts are driedover magnesium sulfate and evaporated. The residue is dissolved in 150parts 2-propanol and gaseous hydrogen chloride is introduced into thesolution. The precipitated salt is filtered off and dried in vacuo,yielding dl-5,6-dihydro-6-phenyl-imidazo [2,l-b] thiazole hydrochloride;M.P. 174176.5 C.

Example XXII A mixture of 36.6 parts of 3-nitro-phenacylbromide, 15parts of Z-amino-thiazole and 160 parts of 2-propanol is stirred andrefluxed for one hour (water-bath). After cooling the reaction mixture,the formed precipitate is filtered 16 off, washed with 2-propanol anddried, yielding 2-irnino- 3-(3-nitro-benzoyl-methyl)-thiazolinehydrobromide; M.P. 245-309 C. (dec.).

Example XXIII A mixture of 45 parts :of2-imino-3-(3-nitro-benzoylmethyl)-thiazoline hydrobromide, 350 parts ofacetic anhydride and 14 parts of anhydrous sodium acetate is stirred andrefluxed for 2 hours. The reaction mixture is cooled, filtered and thefiltrate is evaporated. The oily residue is washed with 400 partsammonium hydroxide solution 10% and extracted with cholorform. Theextract is dried over sodium sulfate, filtered and evaporated. The oilyresidue is triturated in acetone. The solid is recrystallized from 120parts toluene, filtered off and dried, yielding Z-(acetyI-imino) 3(3-nitro-benzoyl-methyl)-thiazoline; M.P. l51152 C.

Example XXIV To a stirred mixture of 13 parts of 2-(acetyl-imino)-3-(3-nitro-benzoyl-methyl)-thiazoline in 200 parts absolute denaturedethanol are added portionwise 4.5 parts of sodium borohydride. After theaddition is complete, the whole is stirred and refluxed for one hour.After cooling the solvent is evaporated. The residue is decomposed with300 parts diluted hydrochloric acid. The solution is filtered andalkalized with ammonium hydroxide solution and then extracted withchloroform. The extract is dried over sodium sulfate, filtered andevaporated. The oily residue is boiled in a mixture of parts of benzeneand 20 parts acetone. After cooling to room temperature, theprecipitated solid is filtered off and dried, yieldingdl-2-(acetylimino) -3- (B-hydroxy-I:-nitro-phenethyl) -thiazoline; M.P.

138.5-154" C. (dec.).

Example XXV 24 parts of thionyl chloride are cooled to a temperature of0 C. While maintaining a temperature between 0-5 C. there are added 7parts ofdI-Z-(acetyl-imino)-3-(,B-hydroxy-3-nitro-phenethyl)-thiazoline. Afterthe addition is complete, the whole is stirred for 2 hours at roomtemperature. Then there are added 75 parts of acetic anhydride at atemperature below 20 C. The formed acetyl chloride is distilled off(oil-bath temperature 136 C.). The residue is evaporated. The oilyresidue is dissolved in parts of hydrochloric acid 10%. The solution isfiltered and the filtrate is alkalized with ammonium hydroxide solutionand extracted with toluene. The extract is dried over sodium sulfate,filtered and evaporated. The oily residue is dissolved in 20 parts ofboiling Z-propanol. To this hot solution is added a warm solution of 1part of oxalic acid dihydrate in 20 parts of 2-propanol. After coolingto room temperature, the precipitated salt is filtered 01f, washed withacetone and dried, yielding dl-5,6-dihydro- 6-(3-nitro-phenyl)-imida2o[2,1-b] thiazole oxalate; M.P. 192195 C.

Example XXVI A mixture of 41.7 parts of 3-bromo-phenacylbromide, 15parts of Z-amino-thiazole and 200 parts of 2-propanol is stirred andrefluxed for one hour in a Water-bath. After cooling the reactionmixture to room temperature, the formed precipitate is filtered off,washed first with 2- propanol and then with boiling methanol, yielding2- imino 3 (3-bromo-benzoyl-methyl)-thiazoline hydrobromide; M.P. 203205C.

Example X X VII To a stirred and cooled (0 C.) solution of 36 parts of2-imino-3-( 3-bromo-benzoyl-metl1yl)-thiazoline hydrobromide in 200parts of methanol are added portionwise 7.6 parts 10f sodiumborohydride, While keeping the temperature between O5 C. After theaddition is complete, the Whole is stirred for one hour at roomtemperature. The precipitated solid is filtered off and the filtrate isevaporated. The combined solids are stirred for 10 minutes in 1 1 80parts of a 25% hydrobromic acid solution. The precipitate is filteredoff, washed with 2-propanol and dried, yieldingdl-2-imino-3-(B-hydroxy-3-bromophenethyl)thiazoline hydrobromide; M.P.245.5-247 C.

Example XXVHI A mixture of 15 parts of dl-2-imino-3-(fi-hydroxy-3-bromo-phenethyl)-thiazoline hydrobromide, 24 parts of thionyl chlorideand 115 parts acetic anhydride is stirred and refluxed for 30 minutes inan oilbath. Then a second portion of 19 parts of thionyl chloride isadded and the whole is stirred and refluxed for a further 30 minutes.The formed acetyl chloride is distilled off in an oil-bath at atemperature of ISO-160 C. in the course of about 2 hours. The residue isevaporated. The oily residue is dissolved in a mixture of 300 parts ofwater and 30 parts of concentrated hydrochloric acid. This solution isboiled for a few minutes with activated charcoal, filtered hot and aftercooling the filtrate to room temperature, a solid is precipitated. It isfiltered 01f (filtrateis set aside) and 7 dried, yieldingdl-Z-(acetyl-imino)-3-(,8-acetoxy-3-bromophenethyD-thiazolinehydrochloride; M.P.143.5149 C.

The filtrate which was set aside is alkalized with ammoniurn hydroxidesolution and extracted with toluene. The extract is dried over sodiumsulfate, filtered and evaporated. The oily residue is dissolved inacetone and this solution is evaporated again. The solid residue isrecrystal-' lized from a mixture of 64 parts benzene and 40 partspetroleum ether, to yield d1 -2(acetyl-imino)-3-(,B-hydroxy-3-bromo-phenethyl)-thiazoline; M.P. 151-152C.

Example XXIX 24 parts of thionyl chloride are stirred and cooled to 0 C.While maintaining the temperature below 10 C., there are addedportionwise 7 parts of dl-2(acetyl-imi11o)-3-(,8-hydroxy-3-bromo-phenethyl)-thiazoline. The mixture is stirred for2 hours at room temperature. Then there are added 75 parts of aceticanhydride at a temperature below C. T he formed acetyl chloride isdistilled off (oil-bath temperature 130 C.). The solvent is evaporated.The oily residue is dissolved in a mixture of 150 parts of water and 15parts of hydrochloric acid. The whole is stirred for a few minutes withactivated charcoal and filtered. The

filtrate is alkalized with ammonium hydroxide and ex tracted withtoluene. The extract is dried over sodium sulfate, filtered andevaporated. The oily residue is dissolved in 60 parts of boiling2-propanol. This solution is filtered hot and to the warm filtrate isadded a hot solution of 1.8 parts of oxalic acid dihydrate in parts of2-propanol. The precipitated salt is filtered off, washed with acetoneand dried, yielding dl-5,6-dihydro-6-(3-brom0 phenyl)-imidazo [2,1-b]thiazole oxalate; M.P. 153- 155" C.

Example XXX A mixture of 17.5 parts of S-chIorO-phenacylbromide, 7.5parts of Z-amino-thiazole and 120 parts of acetonitrile is stirred andheated (Water-bath) for one hour. After cooling the precipitated productis filtered off and dried,

yielding 2 imino-3-(3-chloro-benzoyl-methyl)-thiazoline hydrobromide; M.P. 215-216 C.

Example XXXZ A mixture of 15 parts of 2-imino-3-(3-chloro-benzoylmethyl)-thiazoline hydrobrornide, 13.8 parts of acetic anhydride, 13.8 parts ofpyridine and 275 parts of chloroform is stirred and refluxed for 6hours. After cooling the reaction mixture is washed with ammoniumhydroxide solution; The organic layer is separated, dried andevaporated. The oily residue is crystallized from toluene, yielding2-(acetyl-imino)-3-(3-chloro-benzoyl-methyl)-thiazoline; M.P. 145-147 C.

12 Example XXXII The filtrate is evaporated. The residue is decomposedwith water and extracted with chloroform. The extract is dried oversodium sulfate, filtered and evaporated. The solid residue is trituratedin toluene, yielding a second fraction of dl 2 (acetylirnino)-3-(fi-hydroxy-3-chlor0- phenethyl)-thiazoline; M.P. 141 C.

Example XXXHI T o 16 parts of thionyl chloride are added 6 parts of dl-2'- (acetyl imino) 3-(fi-hydroxy-3-chloro-phenethyl)- thiazoline at atemperature below 10 C. and while stirring. After the addition iscomplete, the whole is stirred for 2 hours at room temperature. Thenthere are added 50 parts of acetic anhydride at a temperature below 15C. The formed actyl chloride is distilled off, whereafter the whole isstirred and refluxed for 2 hours. The mixture is evaporated. The residueis dissolved in 100 parts of Water and 10 parts of hydrochloric acid areadded. The whole is filtered. The filtrate is alkalized with ammoniumhydroxide solution and extracted with toluene. The solvent is dried oversodium sulfate, filtered and evaporated. The oily residue is dissolvedin 60 parts of boiling 2-propanol. To this hot solution is added a warmsolution of 3 parts of oxalic acid dihydrate in 40 parts of 2-propanol.After cooling to room temperature, the precipitated oxalate salt isfiltered off, washed with acetone and dried, yielding dl-5,6-dil1ydro-6-(B-chlorophenyl)-imidazo [2,1-b] thiazole oxalate; M.P.-157 C.

Example XXXIV A mixture of 38 parts of bromo-methyl-2-thionylketone,14.3 parts of 2-amino-4,S-dihydro-thiazole and 1210 parts ofacetonitrile is stirred and heated in a. waterbath for 1 h., 30. Aftercooling, the precipitated product is filtered ofi, Washed on the filterwith acetonitrile and dried, yielding 2-imino-3- (Z-thienyl-carbonyl)-mcthyl] thiazolidine hydrobromide; M.P. 213-2135 C.

Example XXXV To a cooled (0 C.) and stirred solution of 8.5 parts of 2(acetyl irnino)-3-['(2-thionyl-carbonyl)-methyl]- thiazolidine in 80parts of methanol are added portion.- wise 1.3 parts of sodiumborohydride, while keeping the temperature below 5 C. After the additionis complete, 7

the whole is stirred for one hour at room temperature. The reactionmixture is evaporated. The solid residue is decomposed with Water andextracted with chloroform. The extract is dried over sodium sulfate,filtered and evaporated. The oily residue is triturated in acetone. Thesolid is filtered off and dried, yielding dl-2-(acetylimino)-3-[2-(acetyl irnino) 3 [2 lrydroxy-Z-(Z-thionyl)-ethyl]- I thiazolidine; M.P.85.5-88 C.

parts of dl-2- (acetyl-imino)-3-[2-hydroxy-2-(2-thionyl)-ethyl]-thiazolidine are added to 15.4 parts of thionyl chlorideat a temperature below C. After the addition is complete, the Whole isstirred for one hour at room temperature. Then there are added dropwise50 parts of acetic anhydride. The formed acetyl chloride is distilledoff, whereupon the whole is stirred and refluxed for 2 hours. Themixture is evaporated. The residue is dissolved in 100 parts of water.To this solution is added 10 parts of hydrochloric acid. The whole isboiled with activated charcoal and filtered. The filtrate is alkalizedwith ammonium hydroxide and extracted with toluene. The extract is driedand evaporated. The oily residue is dissolved in acetone and gaseoushydrogen chloride is introduced into the solution. The precipitated saltis filtered off and dried, yielding dl-2,3,5,6-tetrahydro-6-(2-thionyl)-irnidazo [2,l-b] thiazole hydrochloride; M.P. 2l6220 C.

Example XXXVIH A mixture of 19 parts bromo-methyl-2-uryl-ketone, 10.2parts of 2-amino-4,S-dihydro-thiazole and 80 parts of acetonitrile isstirred and heated in a Water-bath for 1 h., 30. After cooling thereaction mixture, the precipitated product is filtered off, washed withacetonitrile and dried, yielding 2irnino-3-[(Z-furyl-carbonyl)-methyl]-thiazolidine hydrobromide; M.P.202-203 C.

Example XXXIX A mixture of 2 parts of 2-imino-3-[(2-furyl-carbonyl)-methyl] -thiazolidine hydrobromide, 3.5 parts of acetic anhydride, 3.5parts of dry pyridine and 30 parts of dry chloroform is stirred andrefluxed for 6 hours. After cooling the reaction mixture is washed withammonium hydroxide solution. The organic layer is separated, dried andevaporated. The oily residue is dissolved in 16 parts of Warm toluene.The solution is cooled to room temperature. The solid is filtered offand recrystallized from toluene, yielding 2(acetyl-imino)-3-[(2-furyl-carbonyl)- methyl]-t'hiazolidine; M.P.132-135 C.

Example XL To a solution of 9 parts of 2 (acetyl-imino)-3-[(2-furylcarbonyl)-methyl]-thiazolidine in 80 parts of methanol are addedportionwise 1.8 parts of sodium borohydride at a temperature of 0 C.After the addition is com plete, the whole is stirred for one hour atroom temperature. The reaction mixture is evaporated. The oily residueis dissolved in chloroform. This solution is washed with water, driedand evaporated. The oily residue is triturated in toluene. After keepingat room temperature, the solid is filtered off and dried, yielding dl-2(acetyl-imino)-3- [2 hydroxy 2 (2 furyDethyl] thiazolidine; M.P.110.5112 C.

Example XLI 6 parts of dl 2 (acetyl imino) 3 [2 hydroxy- 2 (2furyl)-ethyl]-thiazolidine are added portionwise to 14.4 parts ofthionyl chloride at a temperature below 10 C. After the addition iscomplete, the mixture is stirred for 2 hours at room temperature. Thenthere are added dropwise 50 parts of acetic anhydride. The formed acetylchloride is distilled off, whereafter the mixture is stirred andrefluxed for 2 hours. The mixture is evaporated. The oily residue isdissolved in 100 parts of water and 10 parts of hydrochloric acid areadded. The whole is boiled with activated charcoal and ffltered. Thefiltrate is alkalized with ammonium hydroxide and extracted withtoluene. The extract is dried over magnesium sulfate and evaporated. Theoily residue is dissolved in parts of Z-propanol. To this boilingsolution is added a hot solution of 3.1 parts of oxalic acid dihydratein 20 parts of 2-propanol. After cooling to room temperature, theprecipitated salt is filtered 0E, yielding dl-2,3,5,6-tetrahydro- 14 6(2 furyD-irnidazo [2,l-b] thiazole oxalate; M.P. 176176.5 C.

Example XLII From an aqueous solution of dl-2,3,5,6-tetrahydro-6(2-furyl)-imidazo [2,1-b] thiazole oxalate, the free base is liberatedin the usual manner. After extraction With toluene, the extract is driedand evaporated. The oily residue is dissolved in acetone and gaseoushydrogen chloride is introduced into the solution. The precipitatedhydrochloride is filtered off and dried, yielding dl-2,3,5,6-tetrahydro-d(2-furyl)-imidazo [2,l-b] thiazole hydrochloride; M.P.206.5209 C.

Example XLIII To a solution of 5.1 parts of 2-arnino-4,5dihydrothiazolein 40 parts of acetonitrile are added portionwise 10 parts ofphenacylbromide (exothermic reaction). After the addition is complete,the mixture is stirred and refluxed for 30 minutes in a water-bath.After cooling the precipitated solid is filtered oil and dried, yielding2-irnino- 3- benzoyl-rnethyl) -thiazolidine hydrobromide; M.P. 200 C.(dec.).

Example XLI V A mixture of 6 parts of Z-imino 3 (benzoyl-methyl)thiazolidine hydrobromide, 3.4 parts of acetic anhydride, 3.4 parts ofdry pyridine and 60 parts of dry chloroform is stirred and refluxed for6 hours. After cooling the reaction mixture is Washed with ammoniumhydroxide solution. The organic layer is separated, dried over magnesiumsulfate and evaporated. The solid residue is recrystallized fromtoluene, yielding 2 (acetyl-imino) 3 (benzoylmethyl)-thiazolidine; M.P.l40-141 C.

Example XLV To a solution of 3.4 parts of 2 (acetyl-irnino) 3-(benzoyl-methyl)-thiazolidine in 24 parts of methanol are addedportionwise 0.5 part of sodium borohydride at a temperature between 5-10C. After the addition is complete, the Whole is stirred for one hour atroom temperature. The reaction mixture is evaporated. The residue isdissolved in water. The solution is extracted with chloroform. Theextract is dried, and evaporated. The solid residue is recrystallizedfrom toluene, yielding dl 2- (acetyl-imino) 3 (,6hydroxy-phenethyl)-thiazolidine; M.P. -1035 C.

Example XLVI 25.6 parts of thionyl chloride are cooled to 10 C. Whilemaintaining this temperature there are added portionwise 11 parts of d12 (acetyl-irnino) 3 (,B-hydroxy-phenethyl)-thiazolidine. The mixture isstirred for 2 hours tt room temperature. After cooling to 10 C., thereare added 75 parts of acetic anhydride. After the addition is complete,the formed acetyl chloride is distilled ofi', whereafter the mixture isstirred and refluxed for 2 hours. The whole is evaporated. The residueis dissolved in a mixture of 20 parts of hydrochloric acid and 260 partsof water. The solution is filtered, cooled and alkalized with ammoniumhydroxide. The separated free base is extracted with toluene. Theobtained solution is dried and evaporated. The oily residue is dissolvedin 40 parts of boiling 2-propanol. To this hot solution is added a warmsolution of 6 parts of oxalic acid dihydrate in 40 parts of 2-propanol.After cooling the precipitated salt is filtered olf and dried, yieldingdl 2,3,5,6-tetrahydro-6- phenyl-imidazo [2,1-b] thiazole oxalate; M.P.195.5- 196 C.

Example XLVII From 6 parts of dl 2,3,5,6 tetrahydro 6 phenylimidazo[2,1-b] thiazole oxalate the free base is liberated in a conventionalmanner and extracted with toluene. After drying, the organic solution isevaporated. The oily 15 .a residue is dissolved in 80 parts of acetoneand gaseous hydrogen chloride is introduced into the solution. Theprecipitated hydrochloride salt is filtered ofi and dried, yielding dl2,3,5,6 tetrahydro 6 phenyl-imidazo [2,1-b] thiazole hydrochloride; M.P.26l.5264.5 C.

Example XLVIII To a stirred and refluxed suspension of 17 parts of 1,2-dibromoethane, 7.8 parts of sodium hydrogen carbonate and 50 parts of2propanol is added a mixture of 3.4 parts of dl 2 thio 1phenyl-imidazolidine, 9 parts of a 20% potassium hydroxide solution in40 parts of 2-propan0l over a period of about one hour. After theaddition is complete, the whole is stirred and refluxed for anadditional 3 hours. The reaction mixture is evaporated. To the residueare added 18 parts of a 15% potassium hydroxide solution. The whole isextracted with toluene. The extract is dried and evaporated. The oilyresidue is dissolved in acetone and gaseous hydrogen chloride isintroduced into the solution. The precipitated solid salt is filteredoif and recrystallized from 2-propanol, yielding d1- 2,3,5,6 tetrahydro6 phenyl-imidazo [2,1-b] thiazole hydrochloride; M.P. 264-266 C.

Example XLIX From an aqueous solution of 1.2 parts of dl-2,3,5,6

'tetrahydro-G-phenyl-imidazo [2,1-b] thiazole hydrochloride the freebase is liberated in the usual manner. After extraction with chloroform,the extract is dried and evaporated. The oily residue is crystallizedfrom 4-methyl-2- pentanone, to yielddl-2,3,5,G-tetrahydro-6-phenyl-imidazo [2,1-b1thiazole; M.P. 9092 C.

Example L To a solution of 18.3 parts of 3-nitro-phenacylbromide in 80parts of acetonitrile are added portionwise 7.75 parts of.2-amino-4,S-dihydro-thiazole (exothermic reaction). After the additionis complete, the mixture is stirred for 30 minutes Without heating. Theprecipitated product is filtered off and dried, yielding2-imino-3-(3-nitro-benzoylmethyl) thiazolidine hydrobromide; M.P. +300C. (dec.).

Example LI A mixture of 20 parts of2fimino-3-(3-nitro-benzoylmethyD-thiazolidine hydrobromide, 11.5 partsof acetic anhydride, 11.5 parts of dry pyridine and 225 parts of drychloroform is stirred and refluxed overnight. After cooling the reactionmixture is washed with ammonium hydroxide solution. The organic layer isseparated, dried and evaporated. The oily residue is crystallized from amixture of toluene and heptane, yielding 2-(acetyl-imino)- 3(3-nitro-benzoyl-methyl) -thiazolidine; M.P. 116-145 C. (dec.). 7

- Example LII To a suspension of 7 parts of 2-(acetyl-imino)-3-(3-nitro-benzoyl-methyl)-thiazlidine in 24 parts of methanol are addedportionwise 0.86 part of sodium borohydride. After the addition iscomplete, the Whole is stirred for 2 hours at room temperature. Theformed precipitate is filtered ofi triturated in Water and extractedwith chloroform. The extract is dried and evaporated. The oily residueis crystallized in toluene, yielding dl-2-(acety1-imino)-3-(fi-hydroxy-S-nitro-phenethyl)-thiazolidine; M.P. 122- 140 C.

Example LIII To 16 parts of thionyl chloride are added 4 parts of dl-2-(acetyl imino)-3-(,8-hydrox -3-nitro-phe'nethyl)-thiazolidine at atemperature below 10 C., While stirring. After the addition is complete,the whole is stirred for 2 hours at room temperature. Then there areadded 40 parts of acetic anhydride. The formed acetyl chloride isdistilled off, whe'reafter the mixture is stirred and refluxed for 2hours. The mixture is evaporated. The residue is dissolved in a mixtureof 100 parts of water and 10 parts of hydrochloric acid. The solution isfiltered. The filtrate is alkalized with ammonium hydroxide solution andextracted with toluene. The extract is dried and evaporated. The oilyresidue is dissolved in 40 parts of boiling 2-propanol. T 0 this hotsolution is added a Warm solution of 2.5 parts of oxalic acid dihydratein 16 parts of 2-propanol. After cooling to room temperature, theprecipitated oxalate salt is filtered olf and washed with acetone, toyield 7 d1-2,3 ,5 ,6-tetrahydro-6-( 3-nitro-phenyl) imidazo [2,1-b]thiazole oxalate; M.P. 183-184 C.

Example LIV To a solution of 21 parts of 3-bromo-phenacylbromide in 60parts of acetonitrile is added dropwise a solution of 7.6 parts of2-amino-4,S-dihydro-thiazole in 60 parts of acetonitrile. After theaddition is complete, the whole is stirred for one hour at roomtemperature. The precipitated product is filtered off and dried,yielding 2-imino-3-(3- bromo-benzoyl-methyl)-thiazolidine hydrobromide;M.P. 252253.5 C.)

Example LV A mixture of 21 parts of2-imino-3-(3-bromo-benzoylmethyl)-thiazolidine hydrobromide, 16.8 partsof acetic anhydride, 16.8 parts of dry pyridine and 275 parts of drychloroform is stirred and refluxed for 6 hours. After cooling, thereaction mixture is washed with ammonium hydroxide solution. The organiclayer is separated, .dried and evaporated. The oily residue is dissolvedin 2-propanol and gaseous hydrogen chloride is introduced into thesolution. The precipitated salt is filtered oil and dried, yielding 2(acetyl-imino)-3-(3-bromo-benzoyl-methyl)-thiazolidine hydrochloride;M.P. 162-165 C. 7

Example LVI To a suspension of 9 parts of 2-(acetyl-imino)-3-(3-bromo-benzoyl-methyl)-thiazolidine hydrochloride in 80 parts of methanolare added 1.81 parts of sodium boro- Example LVII To 16 parts of thionylchloride are added 4.5 parts of' dl-Z-(acetyl-imino) 3v(fi-hydroxy-3-bromo-phenethyl)-' thiazolidine at a temperature below 10C. While stirring. After the addition is complete, the whole is stirredfor 2 hours at room temperature. Then there are added drop- Wise 50parts of acetic anhydride at a temperature below 15 C. After theaddition is complete, the formed acetyl chloride is distilled off,Whereafter the mixture is stirred and refluxed for 2 hours. The reactionmixture is evaporated. The residue is dissolved in a mixture of 100parts of water and 10 parts of hydrochloric acid. The solution isfiltered. The filtrate is alkalized with ammonium hydroxide solution andextracted with toluene. The extract is dried over sodium sulfate andevaporated. The oily resi-;

due is dissolved in acetone and gaseous hydrogen chloride is introducedinto the solution. The precipitated salt is filtered off and driedyielding dl-2,3,5,6-tetrahydro-6-(3 bromo-phenyl)-imidazo [2,1-b]thiazole hydrochloride;

M.P. 194-1955 C.

Example LVIII (3-chloro benzoyl-methyl)-thiazolidine hydrobromide; M.P.276-277 C. (dec.).

Example LIX A mixture of 25 parts of2-irnino-3-(3-chloro-benzoylmethyll-thiazolidine hydrobromide, 15.5parts of acetic anhydride, 15.5 parts of dry pyridine and 300 parts ofdry chloroform is stirred and refluxed overnight. After cooling thereaction mixture is washed with ammonium hydroxide solution. The organiclayer is separated, dried and evaporated. The oily residue iscrystallized in a mixture of toluene and heptane, yielding2-(acetyl-imino)-3-(3- chloro-benzoy1-methyl)-thiazolidine; M.P.90.591.5 C.

Example LX To a stirred and cooled C.) solution of 10 parts of 2acetyl-imino)-3-(3-chloro benzoyl methyl)-thiazolidine in 120 parts ofmethanol are added portionwise 1.52 parts of sodium borohydride at atemperature below 5 C. After the addition is complete, the Whole isstirred for one hour at room temperature. The solvent is evaporated. Theresidue is decomposed with water and extracted with chloroform. Theextract is dried over sodium sulfate, filtered and evaporated. The oilyresidue is crystallized in toluene, yieldingdl-Z-(acetyl-imino)-3-,6-hydroxy-chloro-phenethyl)-thiazolidine; M.P.138-139" C.

Example LXI To 16 parts of thionyl chloride are added 7 parts of d1-2-(acetyl-imino)-3-(fi-hydroxy-3-chrloro phenethyl) thiazolidine at atemperature below 10 C. After the addition is complete, the whole isstirred for 2 hours at room temperature. Then there are added 50 partsof acetic anhydride at a temperature below C. The formed acetyl chlorideis distilled 0E, whereafter the reaction mixture is stirred and refluxedfor 2 hours. The mixture is evaporated. The residue is dissolved in amixture of 10 parts of hydrochloric acid and 100 parts of water. Thesolution is filtered. The filtrate is alkalized with ammonium hydroxideand extracted with toluene. The extract is dried over sodium sulfate,filtered and evaporated. The oily residue is dissolved in 40 parts ofboiling Z-propanol. To this hot solution is added a warm solution of 3parts of oxalic acid dihydrate in 40 parts of 2-propanol. After coolingto room temperature, the precipitated oxalate is filtered off, washedwith acetone and dried, yielding dl-2,3,5,6-tetrahydro-6-(3-chlorophenyl)-imidazo [2,1-b] thiazole oxalate; M.P.168-171 C.

Example LXII Thirteen chickens infected with Ascaridia galli andHeterakis gallinae and having an average body Weight of 1.5 kilograms,are given about 40 mg./ kg. of body weight ofdl-2,3,5,6-tetrahydro-6-phenylimidazo [2,1-b] thiazole hydrochloride bythe following oral routes: in gelatin capsules (7 chickens), in drinkingwater (3 chickens) and mixed with feed (3 chickens). The total output offaeces is collected every day for a period of four days and washed. Theexpelled worms in the faeces are collected by serving, identified andcounted. After the fourth day, the chickens are sacrificed andautopsied. The various internal organs of the digestive tract (e.g.,stomach duodenurn, ilium, colon, etc.) are examined for the presence ofworms. A total absence of worms is observed.

In accordance with the above procedure, similar results are obtained(wherein from about -100 percent expulsion of worms are observed) withdl2,3,5,6-tetrahydro-6-(Z-thienyD-imidazo [2,l-b] thiazolehydrochloride, dl-2,3,5,6-tetrahydro-6-(B-chloro-phenyl) imidazo [2,1-b]thiazole oxalate, dl-2,3,5,6-tetrahydro 6 (3 bromo-phenyl)-imidazo[2,1-b] thiazole hydrochloride,dl-2,3,5,6-tetrahydro-6-(3-nitro-phenyl)-imidazo [2,1-b] thiazoleoxalate, dl-5,6-dihydro-6-phenyl-imidazo [2,1-b] thiazole hydrochloride,d1-5,6-dihydro-6-(Z-thienyl)-imidazo [2,1-b] thiazole hydrochloride, anddl-5,6-dihydro-6- (3-bromo phenyl)-imidazo [2,1-b] thiazole oxalate.

Example LXIII Adult sheep, infected with a variety of worms, are givenoral dosages of various anthelmintica in the quantities listed below.The amount of Worms in the faeces and those remaining in the digestivetract of the killed sheen are determined as in Example LXII.

The results obtained are given in the following table, wherein:

TABLE I COMPOUND I Worm count No. of Dose, sheep mgJkg. TrichostrongylusOstertagia Haemoncus N ernatodirus A B Percent A B Percent A 13 PercentA B Percent C OMPOUN D II 2 40 4, 359 O 100 l -l 11,060 0 100 2 1O 5,581 O 100 7, 364 0 100 1 2. 5 6 D 12 0 245 1 99 COMPOUND III TABLEIContinued COMPOUND I-Oontinued Worm count N r D shzeg mg lg.Strongyloldes Bunostomum Chabertia 'lrrchuris A B Percent A B Percent A13 Percent A B Percent 40 4, 625 100 17 11 60 182 0 100 7 0 100 20 3,252 88 98 2s 2 93 115 1 99 105 31 e0 10 25, 356 3 100 137 34 so 245 o100 5 50 2.5 42 1 98 23 2 91 o 4 n COMPOUND II-Co11tinued COMPOUNDIII-Continued Example LXIV A Adult sheep, infected with Dictyocaulusviviparus and young cattle infected with Diciyo ca ulus filaria areg1ven cznumber of Worms expelled in plastic bag oral dosages of variousanthelmimtco 1n the quantites B=number of worms remaining in thehmgslisted below.

The infection rate is determined by countmg the C X 00 Dictyocauluslarvae found in the faeces obtained over a D 24-hour period.

The treated animals are divided in three groups: CompoundI=dl-2,3,5,6-tetrahydro 6 phenyl-umdazo (1) In the first group theanimals have been tracheot- [2,1-b] thiazole hydrochloride. omisedbefore treatment and a plastic bag is fixed in the Compound II=dl 5,6dihydro-6-(2-thienyl)-imidazo tracheotubus to collect the expelledanimals. After the [2,14 thiazole hydrochloride. fourth day the animalsare sacrificed and autopsied. The Group 1 lungs are examined for thepresence of worms, which are Group 2 as identified above. identified andcounted. Group 3 TABLE II COMPOUND I Animal Number of Dose, Larvaecount/gr. faeces Worm count Group species animals mgJkg.

A B Percent C D Percent COMPOUND II A=number of larvae per gram faecesbefore treatment (1 day).

B=number of larve per gram faeces after treatment (4 days).

Example LX V To a solution of 11.5 parts of 2-chloro-acetophenone inparts chloroform are added dropwise 4 parts bromine. After the additionis complete, the whole is stirred for one hour at room temperature. Thechloroform layer is washed with a sodium hydrogen carbonate solution,dried over sodium sulfate, filtered and to the filtrate are added 7.5parts 2-amino-4,5-dihydro-thiazole and 120 parts acetonitrile. The wholeis stirred for 30 minutes at room temperature. The formed precipitate isfiltered off, Washed with acetonitrile and dried, yielding Z-imino-S- (2chloro-benzoyl-methyl)-thiazolidine hydrobromide: MP. 197-l98 C.

A mixture of 15 parts 2-imino-3-(2-ch1oro-benzoylmethyl)-thiazolidinehydrobromide, 15 parts acetic anhy.

dride, 15 parts dry pyridine and 225 parts dry chloroform is stirred andrefluxed for 6 hours. After cooling the reaction mixture is alkalizedwith ammonium hydroxide solution. The chloroform layer is separated,dried over sodium sulfate, filtered and evaporated. The oily residue iscrystallized from 64 parts toluene, yieldingZ-(acetylimino)-3-(2-chloro-benzoyl-methyl) thiazolidine; M.P. 116116.5C.

To a suspension of 8 parts 2-(acetyl-imino)-3-(2-chloro-benzoyl-methyl)-thiazolidine in 120 parts methanol are added 1.5parts sodium tetrahydridoborate at a temperature below C. After theaddition is complete, the Whole is stirred for one hour at roomtemperature. The formed precipitate is filtered OE and dried, yieldingdl-2-(acetyl-imino)-3-(/3-hydroxy 2 chloro-phenethyD- thiazolidine; M.P.163164 C.

To 16 parts thionylchloride are added 5.5 parts dl-2(acetyl-imino)-3-(;3-hydroxy 2 chloro-phenethyl)-thiazolidine at atemperature below C., while stirring. After the addition is complete,the Whole is stirred for 2 hours at room temperature. Then there areadded 50 parts acetic anhydride at a temperature below C. The whole isstirred and refluxed for 2 hours, while the formed acetylchloride isdistilled off (oil-bath: temperature about 136 C.). The mixture isevaporated. The residue is dissolved in a mixture of 100 parts Water and10 parts hydrochloric acid. The solution is filtered. The filtrate isalkalized with ammonium hydroxide solution and extracted with toluene.The extract is dried and evaporated. The oily residue is dissolved in 40parts boiling 2-propanol. To this hot solution is added a Warm solutionof 2 parts oxalic acid dihydrate in parts Z-propanol. After cooling toroom temperature, a semi-solid oxalate is precipitated. The 2-propanolis evaporated. The oily residue is crystallized from acetone, to yielddl-2,3,5,6-tetrahydro 6-(2-chloro-pheny1)-imidazo [2,1-b] thiazoleoxalate; M.P. 157-170 C. (dec.).

Example LX VI From an aqueous solution of 1.25 partsdl-2,3,5,6-tetrahydro-6-phenyl-imidazo [2,1-b] thiazole hydrochloride,the free base is liberated by treatment with ammonium hydroxide. Afterextraction with chloroform, the extract is dried and evaporated. Theoily residue is crystallized from 4-methyl-2-pentanone, to yielddl-2,3,5,6-tetrahydro-6-phenyl-imidazo [2,1-b] thiazole; M.P. 90-92 C.,which is then converted in the usual manner to the correspondingnitrate.

A mixture of 6 parts of dl-2,3,5,6-tetrahydro-6-phenylimidazo [2,1-b]thiazole nitrate and 110 parts of sulphuric acid is stirred for 5 daysat room temperature. Then the mixture is poured onto crushed ice. Thewhole is alkalized with ammonium hydroxide solution and then extractedwith chloroform. The extract is dried over magnesium sulfate andevaporated. The oily residue is dissolved in 120 parts toluene and tothis solution is added 2-propanol previously saturated with gaseoushydrogen chloride. The precipitated solid is filtered off andrecrystallized from 40 parts of ethanol, yieldingdl-2,3,5,6-tetrahydro-6-(4- nitro-phenyl)-imidazo [2,1-b] thiazolehydrochloride; M3 2035-206 C. (dec.).

Example LXVII A mixture of 31 parts ofbromomethyl-4-fluoro-phenylketone, 14.5 parts of2-amino-4,5-dihydro-thiazole and 120 parts of acetonitrile is stirredfor one hour at room temperature. The precipitated product,2-imino-3-(4- fluoro-benzoyl-methyl)-thiazolidine hydrobromide, isfiltered off, Washed on the filter With acetone and dried; M.P. 209-210C.

A mixture of 37 parts of 2-imino-3-(4-fiuoro-benzoylmethyl)-thiazolidinehydrobromide, 40.8 parts of acetic anhydride, 40.8 parts of dry pyridineand 750 parts of dry chloroform is stirred and refluxed for 14 hours.After cooling the reaction mixture is Washed successively with dilutedammonium hydroxide solution and with water. The chloroform is dried overmagnesium sulfate, filtered and evaporated. The solid residue isrecrystallized from 56 parts of toluene, yieldingZ-(acetyl-imino)-3-(4-fiuorobenzoyl-methyl)-thiazolidine; M.P. 126127 C.

To a cooled (0 C.) and stirred suspension of 24 parts of 2-(acetyl-imino -3- (4-fiuoro-benzoyl-methyl) -thiazolidine in 400 partsof methanol is added portionwise 6.5 parts of sodium borohydride. Afterthe addition is complete, the cooling-bath is removed and the whole isstirred for one hour at room temperature. The solvent is evaporated. Theresidue is divided between water and chloroform. The chloroform layer isdried over sodium sulfate, filtered and evaporated. The oily residue iscrystallized from 40 parts of toluene, filtered off and dried, yieldingd1 2 (acetyl-imino)-3-(fl-hydroxy-4-fluoro-phenethyl)- thiazolidine;M.P. 118-121 C.

To a stirred solution of 15 parts of dl-2-(acetyl-imino)-3-(,B-hydroxy-4-fluoro-phenethyl)-thiazolidine in 60 parts of drychloroform is added dropwise 6.8 parts of thionylchloride at atemperature of 30 C. After the addition is complete, the whole isstirred for one hour at 30 C. Then there is added dropwise a solution of21.9 parts of potassium carbonate in 40 parts of Water at roomtemperature and after the addition is complete, the whole is furtherstirred for one hour at room temperature, followed by stirring andrefluxing for 1 hr. 30 min. After cooling there is added parts of water.The chloroform layer is separated, dried over potassium carbonate,filtered and evaporated. The oily residue is dissolved in 16 parts of2-propanol. To this solution is added 2-propanol previously saturatedwith gaseous hydrogen chloride. The precipitated product is filtered offand recrystallized from 2-propanol, to yield dl-2,3,5,6-tetrahydro-6-(4-fluoro-phenyl)-imidazo [2,1-b] thiazole hydrochloride; M.P. 249-252 C.

Example LXVIII A mixture of 49 parts of bromomethyl-l-naphthyl-ketone,20.4 parts of 2-amino-4,5-dihydro-thiazole and 120 parts of acetonitrileis stirred for 1 hr. 30 min. at room temperature. The precipitatedproduct is filtered ofl", washed with acetone and dried, yielding2-imino-3-(1- naphthoyl-methyl) -thiazolidine hydrobromide; M.P. 192-202 C.

A mixture of 31 parts of 2-imino-3-(l-naphthoyl-methyl)-thiazolidinehydrobromide, 30.8 parts of acetic anhydride, 30.6 parts of dry pyridineand 750 parts of dry chloroform is stirred and refluxed for 15 hours.After cooling the reaction mixture is Washed with diluted ammoniumhydroxide solution. The chloroform layer is separated, dried overmagnesium sulfate, filtered and evaporated. The residue is crystallizedfrom 32 parts of toluene, filtered 0E and dried, yielding 2-acetyl-imino)-3-(1- naphthoyl-methyl)-thiazolidine; M.P. 104-1225 C.

To a cooled (0 C.) and stirred suspension of 18 parts of2-(acetyl-irnino)-3-(l-naphthoyl-rnethyl) thiazolidine in 400 parts ofmethanol is added 46 parts of sodium borohydride. The cooling-bath isremoved and the mixture is stirred for one hour at room temperature. Thesolvent is evaporated. The residue is treated with water and thenextracted With chloroform. The extract is dried over magnesium sulfate,filtered and evaporated. The solid residue is recrystallized from 80parts of toluene, filtered off again and dried, yieldingdl-2-(acetyl-imino)-3-[2-hydroxy-Z-(l-naphthyl) ethyl] thiazolidine;M.P. 176- 184 C.

To a stirred solution of 11.2 parts of dl-2-(acetylimino)-3-[2-hydroxy-2-(1-naphthyl)-ethyl] thiazolidine in 60 parts ofdry chloroform is added dropwise 4.6 parts of thionylchloride at atemperature of 30 C. After the addition is complete the Whole is stirredfor one hour at 30 C. Then there is added dropwise a solution of 14.7parts of potassium carbonate in 40 parts of Water at room temperatureand after the addition is complete, the whole is further stirred for onehour at room temperature, followed by stirring and refluxing for 1 hr.30 min. After cooling there is added 100 parts of water. The chloroformlayer is separated, dried over potassium carbonate, filtered andevaporated. The oily residue is dissolved in 60 parts of boiling2-propanol. To this hot solution is added a warm solution of 4.5 partsof oxalic acid dihydrate in 40 parts of 2-propanol. After cooling toroom temperature, the precipitated product is filtered off and dried,yielding dl-2,3,5,6-tetrahydro-6-(l-naphthyl)-irnidazo [2,1-b] thiazoleoxalate; M.P. 175-182 C.

Example LXIX A mixture of 57 parts of bromomethyl-Z-nitro-phenylketone,23.5 parts of 2-amino-4,S-dihydro-thiazole and 240 parts of acetonitrileis stirred for 1 hr. 30 min. at room temperature. The formed precipitateis filtered off, washed with acetone and dried, yielding2-imino-3-(2-nitro-benzoylmethyl)-thiazolidine hydrobromide; M.P. 188.4-191.4 C.

A mixture of 50 parts of 2-imino-3-(Z-nitro-benzoylmethyl)-thiazolidinehydrobromide, 61.2 parts of acetic anhydride, 61.2 parts of dry pyridineand 750 parts of dry chloroform is stirred and refluxed for 8 hours.After cooling the reaction mixture is washed with diluted ammoniumhydroxide and with water. The organic layer is separated, dried oversodium sulfate, filtered and evaporated. The solid residue isrecrystallized from toluene, to yield2-(acetyl-imino)-3-(2-nitro-benzoylmethyl)-thiazolidine; M.P. 120-123.5C.

A stirred suspension of 25 parts of 2-(acetyl-irnino)-3-(Z-nitro-benzoyl-methyl)-thiazolidine in 400 parts of methanol is cooledto 10 C. While maintaining the temperature between 10 and 20 C., thereis added portionwise 4.6 parts of sodium borohydride. After the additionis complete, the whole is stirred for 1 hr. 30 min. The solution isfiltered from some insoluble matter and the filtrate is evaporated. Theresidue is decomposed with water and extracted with chloroform. Theextract is dried over potassium carbonate, filtered and evaporated. Thesemi-solid residue is crystallized from 48 parts of toluene, yielding dl2 (acetyl-imino)-3-(18-hydroxy-2- nitro-phenethyl)-thiazolidine; M.P.119'120 C.

To a stirred solution of 10 parts of dl-2-(acetyl-irnino)-3-(B-hydroxy-Z-nitro-phenethyl)-thiazo1idine in 60 parts of drychloroform is added dropwise 4.1 parts of thionylchloride at atemperature of 30 C. After the addition is complete, the whole isstirred for one hour at 30 C. Then there is added dropwise a solution of13.4 parts of potassium carbonate in 40 parts of water at a temperatureof about 25 C. (cooling in a water-bath) and after this addition iscomplete, the whole is stirred for one hour at room temperature,followed by stirring and refluxing for one hour. The reaction mixture iscooled and then there is added 150 parts of water. The chloroform layeris separated, dried over potassium carbonate, filtered and evaporated.The oily residue is dissolved in 80 parts of boiling 2-propanol. To thishot solution is added a warm solution of 3.5 parts of oxalic aciddihydrate in 40 parts of 2-propanol. After cooling to room temperature,the precipitated solid is filtered off, washed with acetone and dried,yielding dl-2,3,5,6-tetrahydro-6- (2-nitro-phenyl)-imidaz0 [2,1-b]thiazole oxalate; M.P. 173.5175.5 C. (dec.).

Example LXX A solution of parts of dl-2,3,5,6-tetrahydro-6-(4-nitro-phenyl)-imidazo [2,l-b] thiazole hydrochloride in 200 parts ofmethanol is filtered over activated charcoal. The filtrate is added to10 parts of a 30% 2-propanol/ hydrochloric acid solution and the wholeis hydrogenated at normal pressure and at room temperature in thepresence of 3 parts of palladium-on-charcoal catalyst 10%. After thecalculated amount of hydrogen is taken up (3 moles), hydrogenation isstopped. The catalyst is 24 filtered off and the filtrate is evaporated,to yield d1- 2,3,5,6-tetrahydro-6-(4-amino-phenyl) imidazo [2,1-b]thiazole dihydrochloride; M.P. 245-250 C. (-dec.).

Example LXXI A mixture of parts ofbromomethyl-3-trifluoromethyl-phenyl-ketone, 25 parts of2-amino-4,5-dihydrothiazole and parts of 2-propanol is stirred for onehour at room temperature. The precipitated product is filtered off,washed with 2-propanol and dried, yielding Z-amino- 3 (3-trifluoromethyl-b enzoyl-methyl -thiazolidine hydrobromide; M.P.259263.5 C.

A mixture of 58 parts of2-imino-3-(3-trifluoromethylbenzoyl-methyl)-thiazolidine hydrobromide,32 parts of acetic anhydride, 32 parts of dry pyridine and 750 parts ofdry chloroform is stirred and refluxed for 8 hours. After cooling thereaction mixture is Washed with ammonium hydroxide solution and thenwith water. The organic layer is separated, dried over magnesiumsulfate, filtered and evaporated. The oily residue solidifies ontreating with 48 parts of toluene. The solid is filtered off, washedwith toluene and dried, yielding 2-(acetylimino) 3 (3tritiuoromethyl-benzoyl-methyl)-thiazolidine; M.P. 108109 C.

To a solution of 30 parts of 2-(acetyl-imino)-3-(3 residue is decomposedwith water and extracted with chloroform. The extract is dried overmagnesium sulfate, filtered and evaporated. The solid residue isrecrystallized from 64 parts of toluene, to yield dl-2-(acetyl-imino)-3-(fi-hydroxy-3-trifiuoro methyl phenethyl)-thiazolidine; M.P. 142143 C.

To a stirred suspension of 22 parts of d1-2-(acetylimino)-3-(B-hydroxy 3trifluoromethyl phenethyl)- thiazolidine in 120 parts of dry chloroformis added dropwise 8.6 parts of thionylchloride at a temperature below 30C. After the addition is complete, the whole is stirred for one hour atroom temperature. Then there is added dropwise at room temperature asolution of 27.5 parts of potassium carbonate in 80 parts of water andthe whole is stirred for one hour, followed by stirring and refluxingfor one hour. After cooling the reaction mixture, there is added partsof water. The chloroform layer is separated, dried over potassiumcarbonate, filtered and evaporated. The oily residue is dissolved in 48parts of 2-propanol. To this solution is added 2-propanol previouslysaturated wtih gaseous hydrogen chloride. The precipitated solid isfiltered 01f (filtrate is set aside) and dried, yielding a firstfraction of dl-2,3,5,6-tetrahydro- 6-(3-trifluoromethyl-phenyl)-imidazo[2,1-b] thiazole hydrochloride; M.P. 173-179 C.

The mother-liquor is evaporated. The solid residue is recrystallizedfrom a mixture of 40 parts of methanol and parts of ether, yielding,after filtration, a second pure fraction ofdl-2,3,5,6-tetrahydro-6-(3-trifiuoromethyl-phenyl)-imidazo [2,1-b]thiazole hydrochloride; M.P. 173174.5 C. To the latter mother-liquor(methanol/ether filtrate) is added 240 parts of ether,rwhereupon a solidis precipitated. It is filtered off and dried, yielding a third fractionof dl-2,3,5,6-tetrahydro-6-(3- trifluoro-methyl-phenyl)-imidazo [2,1-b]thiazole hydrochloride; M.P. 171-174 C.

Example LXXII An aqueous solution of 21 parts of dl-l,2-diamino-3-phenyl-propane dihydrochloride in 25 parts of water is alkalized withsodium hydroxide and extracted with 20 parts of ethanol. Theprecipitated sodium chlorideis 25 there is added one part ofconcentrated hydrochloric acid and the whole is further stirred forhours at 100 C. After cooling the precipitated product is filtered off,washed with Water and recrystallized from 240 parts of4-methyl-2-pentanone, yielding dl-2-mercapto-4-benzyl-2- imidazoline;M.P. 152-1545 C.

A suspension of 7.5 parts of dl-2-rnercapto-4-benzyl-2- imidazoline,1.15 parts of lithiumamide in 160 parts of xylene is stirred andrefluxed for minutes. After cooling the mixture is added to a solutionof 10.4 parts of 1,2-dibromo-ethane in 40 parts of xylene. After theaddition is complete, the whole is stirred and refluxed for 30 minutes.Then there is added 10 parts of pyridine and the whole is furtherstirred and refluxed for another 30 minutes. After cooling the reactionmixture, there is added successively 100 parts of water and parts ofammonium hydroxide. The aqueous layer is separated and extracted twicewith chloroform. The combined organic layers are died over magnesiumsulfate and evaporated in vacuo. The oily residue is dissolved in2-propanol and to this solution is added 2-propanol previously saturatedwith gaseous hydrogen bromide. The precipitated product is filtered offand dried in vacuo, yielding dl-2,3,5,6-tetrahydro-6-benzyl-imidazo[2,1-b] thiazole hydrobromide; M.P. 2DO205.5 C.

Example LXXIII To a stirred mixture of 66.6 parts of2,3,4-trichloroacetophenone in 225 parts of dry chloroform is addedportionwise 48 parts of bromine (exothermic reaction: temperature risesfrom 20 to 35 C.). After the addition is complete, the whole is stirredfor 15 minutes at room temperature. The reaction mixture is washedsuccessively with water, sodium hydrogen carbonate and water. Thechloroform layer is dried over magnesium sulfate and filtered. Thefiltrate is evaporated, yielding 2,3,4-trichloro-phenacylbromide, whichis used without further purification for the next step.

A mixture of 90.7 parts of 2,3,4-trichloro-phenacylbromide, 30 parts of2-amino-4,S-dihydro-thiazole and 160 parts of 2-propanol is stirred forone hour at room temperature. The precipitated product is filtered 01f,washed with 2-propanol and dried, yielding 2-imino-3-(2,3,4-trichloro-benzoyl-methyl)-thiazolidine hydrobromide; M.P.282-283 C.

A mixture of 53.5 parts of 2-imino-3-(2,3,4-trichlorobenzoyl-methyl)-thiazolidine hydrobromide, 27 parts of acetic anhydride,27 parts of dry pyridine and 750 parts of dry chloroform is stirred andrefluxed for 7 hours. After cooling the reaction mixture is washedsuccessively with diluted ammonium hydroxide solution and with water.The organic layer is separated, dried over magnesium sulfate, filteredand evaporated. The oily residue is crystallized from 60 parts oftoluene, yielding a first fraction of2-(acetyl-imino)-3-(2,3,4-trichloro-benzoylmethyl)-thiazolidine; M.P.128.5170.5 C. (dec.).

The mother-liquor is evaporated. The residue is crystallized from 40parts of toluene. The obtained solid is filtered off, boiled for a fewminutes in 80 parts of hexane, filtered off while hot and dried, toyield a second fraction ofZ-(acetyl-imino)-3-(2,3,4-trichloro-benzoyl-methyl)-thiazolidine; M.P.122.5126 C.

To a stirred and cooled (0 C.) suspension of 21.5 parts ofZ-(acetyI-imino) 3 (2,3,4-trichloro-benzoyl-methyl)- thiazolidine in 400parts of methanol is added portionwise 4.6 parts of sodium borohydride.The mixture is allowed to come to room temperature and then stirred forone hour. The whole is filtered and the filtrate is evaporated. Theresidue is treated with water and extracted with chloroform. The extractis dried over magnesium sulfate, filtered and evaporated. The oilyresidue is crystallized from 40 parts of toluene. The solid is filteredoff and dried, yielding dl-2-(acetyl-imino)-3-(3-hydroxy-2,3,4-trichloro-phenethyl)-thiazolidine; M.P. 156-156.5 C.

To a stirred solution of 11.5 parts of dI-Z-(acetylimino) 3 (Bhydroxy-2,3,4-trichloro-phenethyl)-thiazolidine in 75 parts of drycholoroform is added dropwise 4.2 parts of thionylchloride at atemperature below 30 C. After the addition is complete, the whole isstirred for one hour at room temperature. Then there is added dropwise asolution of 13.8 parts of potassium carbonate in 50 parts of water atroom temperature. After this addition is complete, the whole is stirredand refluxed for one hour. The mixture is cooled and there is added 50parts of water. The chloroform layer is separated, dried over magnesiumsulfate, filtered and evaporated. The oily residue solidifies ontreating in acetone. The precipitated solid is filtered off and dried,yielding a first fraction of dl-2,3,5,6-tetrahydro-6-(2,3,4-trichlorophenyl)-imidazo [2,1-b] thiazolehydrochloride; M.P. 244.5254 C.

The mother-liquor (acetone filtrate) is evaporated. The residue isdissolved in 250 parts of diluted hydrochloric acid. To this solution isadded activated charcoal and the Whole is stirred and heated for a fewminutes. The charcoal is filtered ofi while hot and after cooling thefiltrate to room temperature, a second fraction is precipitated. It isfiltered off and dried, yielding dl-2,3,5,6-tetrahydro-6-(2,3,4-trichloro-phenyl)-irnidazo [2,1-b] thiazole hydrochloride; M.P.255-2565 C.

The latter mother-liquor is alkalized and extracted with toluene. Theextract is dried over magnesium sulfate, filtered and evaporated. Theoily residue is dissolved in parts of acetone and gaseous hydrogenchloride is introduced into the solution. The precipitated solid isfiltered off and dried, yielding a third fraction ofdl-2,3,5,6-tetrahydro-6-(2,3,4-trichlorophenyl)-irnidazo [2,1-b]thiazole hydrochloride; M.P. 2615-264 C.

Example LXXIV A mixture of 43.5 parts 4-(2-bromo-acetyl)-fluor0benzene,20 parts Z-amino-thiazole and 160 parts 2-propanol is stirred andrefluxed for one hour in a water-bath. After cooling the reactionmixture the formed precipitate is filtered off, washed with 2-propanoland dried, yielding 2 imino-3-[(4-fiuoro-benzoyl)-methyl]-thiazolinehydrobrornide; M.P. 235237.5 C.

To a mixture of parts 2 imino 3 [(4 fluorobenzoyl)-methyl]-thiazolinehydrobromide and 320 parts methanol are added portionwise 12 partssodium tetrahydridoborate, while keeping a temperature of 0 C.(icebath). After the addition is complete (slightly exothermicreaction), the mixture is stirred for one hour at room temperature. Theprecipitated solid is filtered off and the filtrate is evaporated. Thecombined solids are stirred for 10 minutes with 175 parts hydrobromicacid 25%. The precipitated salt is filtered off, washed with 2-propanoland dried, yielding dl-2-imino3-[2-hydroxy-2-(4-fiuorophenyl) ethyl]thiazoline hydrobromide; M.P. 196- 203" C.

A mixture of 10 parts dl-2-imino-3-[2-hydroxy-2-(4-fiuoro-phenyl)-ethyl]-thiazoline hydrobrornide, parts acetic anhydrideand 15 parts thionylchloride is stirred and refluxed for 30 minutes.Then a second portion of 10 parts thionylchloride is added and the wholeis stirred and refluxed for another 30 minutes. The formedacetylchloride is distilled oif in an oil-bath at a temperature of about160 C. in the course of about 2 hours. The solvent is evaporated. Theoily residue is treated with 200 parts water and 10 parts dilutedhydrochloric acid. The Whole is boiled with activated charcoal, filteredand the filtrate is alkalized with ammonium hydroxide and extracted withtoluene. The extract is dried and evaporated. The oily residue isdissolved in parts boiling 2-propanol. To this hot solution is added awarm solution of 3.6 parts oxalic acid dihydrate in 80 parts 2-propanol.After cool ing to room temperature, the precipitated solid oxalate isfiltered off and dried, yielding dl-5,6-dihydro-6-(4- fluoro-phenyl)-imidazo [2,1-b] thiazole oxalate; M.P. 168-173 C.

27 Example LXX V A mixture of 13.5 parts 4-nitro-phenacylbromide, 7.1parts Z-(acetyl-amino)-thiazole and 80 parts toluene is heated in asealed tube for about 96 hours at a temperature between 105-115 C. Theformed precipitate is filtered oft", washed with boiling toluene andrecrystallized from 120 parts methanol, yielding 2-(acetyl-imino)-3-(4-nitro-benzoyl-methyl)-thiazoline hydrobromide; M.P. 216-218 C.

To a cooled C.) solution of 11 parts Z-(acetylimino)-3-(4 nitro benzoylmethyl)-thiazoline hydrobromide in 80 parts methanol are addedportionwise 2.3 parts sodium tetrahydridoborate at a temperature belowC. After the addition is complete, the mixture is stirred for one hourat room temperature. The formed precipitate is filtered oif, washed withdiluted ammonium hydroxide solution and dried, yieldingdl-2-(acetyl-imino)-3-(,6- hydroxy-4-nitro-phenethyl)-thiazoline; M.P.238-246 C.

24 parts thionylchloride are cooled to 0 C. While maintaining thetemperature below C., there are added 11 partsdl-2-(acetyl-imino)-3-(fi-hydroxy-4-nitrophenethyl)-thiazoline. Afterthe addition is complete, the whole is stirred for 2 hours at roomtemperature. Then there are added 75 parts acetic anhydride at atemperature below C. After this addition is complete, the whole isheated in an oil-bath for 2 hours at a temperature of 136 C., duringwhich time the excess acetylchloride is removed. The solvent isevaporated. The residue is dissolved in a mixture of 150 parts water and15 parts diluted hydrochloric acid. This solution is filtered, alkalizedwith ammonium hydroxide solution and extracted with toluene. The extractis dried over sodium sulfate, filtered and evaporated. The oily residueis dissolved in 80 parts boiling 2-propanol. To this hot solution isadded a warm solution of 3 parts oxalic acid dihydrate in 40 parts2-propanol: an oil is precipitated. The solvent is decanted (oilyresidue is set aside) and after keeping at room temperature, a solidoxalate is formed. It is filtered oil and dried, yielding a firstfraction of (ll-5,6- dihydro 6 (4-nitro-phenyl)-imidazo [2,1-b] thiazoleoxalate; M.P. l57l58 C. The oily residue, which was set aside, iscrystallized from 120 parts methanol. The solid is filtered oil anddried, yielding a second fraction ofdl-5,6-dihydro6(4-nitro-phenyl)-imidazo [2,l-b] thiazole oxalate; M.P.l56-157.5 C.

Example LXXVI 5 parts of water are added to a stirred, cooled solutionof 5 parts of dl-o-phenyl 2,3,5,6 tetrahydro imidazo [2,1-b] thiazole in40 parts of Z-S-methoxyethylpyridine. There is thus obtained a solutionwhich, after suitable dilution, is suitable for oral administration toanimals, and, after sterilization, is suitable for parenteraladministration to animals, for the treatment of helminthiasis.

Example LXXVII A mixture of 4 parts of hydroxylamine hydrochloride and 1part of the sodium salt of ethylenediamine tetraacetic acid is dissolvedin 400 parts of water, and the solution is cooled. The solution isstirred and 120 parts of sulphuric acid are slowly added. 360 parts of2-5- methoxy-ethylpyridine and 36 parts of dl-6-phenyl-2,3,5,6-tetrahydro-imidazo [2,l-b] thiazole hydrochloride are then addedsuccessively to the stirred solution. The final volume of the solutionis adjusted to 1000 ml. by the addition of water. There is thus obtaineda drench suitable for oral administration to animals for the treatmentof helminthiasis.

Example LXXVIII An aqueous solution containing 100 parts of 2- 3-methoxyethylpyridine and 15 parts of dl-6-phenyl-2,3,5,6-tetrahydro-imidazo [2,l-b] thiazole hydrochloride is administered orallyat a dose of 100 mg./ kg. (of body Weight) of 2-,B-methoxyethylpyridineand 15 mg./kg. (of

body weight) of dl-6-phenyl-2,3,5,6-tetrahydro-imidazo [2,1-b] thiazolehydrochloride to sheep carrying infestations of Haemonchus spp.,Ostertagia spp., Trichostrongylus spp., Cooperia spp., Nemadodirus spp.,Oesophagostomum spp., Trichuris spp. and Chabertia spp. The animals aresacrificed 7 days after being dosed, and postmortem examination showsthat the percentage reduction in worm burden of each species is betweenand compared with untreated control animals.

What is claimed is:

1. An anthelmintic composition comprising an effective amount of animidazo [2,l-b] thiazole in admixture with a pharmaceutical carrier,said imidazo [2,1-b] thiazole selected from the group consisting of J VI and the therapeutically acceptable acid addition salts thereof,wherein the dotted line between the 2- and 3-positions of the imidazo[2,1-b] thiazole nucleus represents an optional bond and Ar is a memberselected from the group consisting of thienyl, fvuryl, phenyl,halophenyl, nitrophenyl, aminophenyl, trifluorornethylphenyl, naphthyland benzyl, provided that when said Ar is benzyl, a saturated bondexists between the 2- and 3-positions of the imidazo [2,1-b] thiazolenucleus.

2. The anthelmintic composition of claim 1 wherein said compound is atherapeutically acceptable acid addition salt ofdl-2,3,5,6-tetrahydro-6-phenyl-imidazo [2,l-b] thiazole.

3. The anthelmintic composition of claim 1 wherein the compound is atherapeutically acceptable acid addition salt ofdl-5,6-dihydro-6-phenyl-imidazo [2,1- b] thiazole.

4. The anthelmintic composition of claim 1 wherein the compound is atherapeutically acceptable acid addition salt ofdl-5,6-dihydro-6-(Z-thienyl)-imidazo [2,1-b] thiazole. I

5. The anthelmintic composition of claim 1 wherein the compound is(ll-2,3,5,6-tetrahydro-o-phenyl-imidazo [2,1-b] thiazole hydrochloride.

6. The anthelmintic composition of claim 1 wherein the compound isdl-5,6-dihydro-6-phenyl-imidazo [2,1b] thiazole hydrochloride.

7. The anthelmintic composition of claim 1 wherein the compound isdl-5,6-dihydro-6-(2-thienyl)-imidazo [2,l-b] thiazole hydrochloride.

8. The method of killing helminths which comprises administering toinfected subject an anthelmintic amount of an imidazo [2,1-b] thiazoleselected from the group consisting of and the therapeutically acceptableacid addition salts thereof, wherein the dotted line between the 2- and3-positions of the imidazo [2,1-b] thiazole nucleus represents anoptional bond and Ar is a member selected from the group consisting ofthienyl, furyl, phenyl, halophenyl,

29 thiazole is a therapeutically acceptable acid addition salt ofdl-2,3,5,6-tetrahydro-6-phenyl-imidazo [2,1-b] thiazole.

10. The method of claim 8 wherein the imidazo [2,1-b] thiazole is anacid addition salt of dl-5,6-dihydr0- 6-phenyl-imidazo [2,1-b] thiazole.

11. The method of claim 8 wherein the imidazo [2,1-b] thiazole is atherapeutically acceptable acid addition salt ofd1-5,6-dihydr0-6-(Z-thienyl)-imidazo [2,1-b] thiazole.

References Cited UNITED STATES PATENTS 12/ 1956 Bosk-amp 16755 7/1957Forrest et al 167-55 1/1961 Krimmel 260306.7 9/ 1964 Szmuszkovicz260306.7

ALBERT T. MEYERS, Primary Examiner.

10 R. S. BARRESE, Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,364,112 January 16, 1968 Alfons Herman Margaretha Raeymakers et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 3, line 23, for "-6-A-imidazo" read -6Ar imidazo column 7, line75, for "thiazolo" read thiazole H column 12, lines 73 and 74, strikeout "-3- [Z-(acetylimino)"; column 14, line 53, for "tt" read at column15, line 11, for "thio-l-phenyl" read thio-4-phenyl column 17 line 24before 8'' insert an opening parenthesis column 18, line 11, for"serving" read seiving line 31, for "anthelmintica" read anthelminticscolumns 17 and 18, TABLE I, third column, line 3 thereof, for "12,923"read 12,928 column 19, line 29, for "anthelminitco" read anthelminticscolumn 25, line 19, for "died" read dried column 28, line 33, for "said"read the column 29, line 5, for "an" read a therapeutically acceptableSigned and sealed this 1st day of April 1969.

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents EDWARD M.FLETCHER,JR.Attesting Officer

